Natural products serve as safe and effective therapeutic agents for the drug discovery. Plants produce bioactive secondary metabolites such as terpenoids, alkaloids, tannins, saponins, and others, which have profusely been studied for anti-infective, anticancer, anti-inflammatory potential, and metabolic disorders to name a few. Terpenoids constitute the largest class of natural compound. The study investigates the novel cytotoxic compound of the terpenoid family isolated from different natural sources. The anticancerous activities of the compounds discussed in this review are taken from the published articles showing activity against specific cancer cell lines. The compounds exclusively belong to terpenoid family. Considering the huge potential of plant-based natural products in drug discovery program and the contribution of terpenoid in the production of anticancer compounds, it can be exploited for more reliable economical and environmentally safe bioactive molecules.

Cancer is the uncontrolled unregulated growth of cells that generally invade and destroy normal cells. Cancer alone accounts for 2%–3% of the total death occurring across the globe. About 3500 million people lose their life every year suffering from cancer worldwide. Although major treatments include usage of chemopreventive agents, it is of limited use by toxic effect that damages body tissues.[1] Products obtained from natural sources have always plays a vital role in treating and checking human diseases since ancient times.[2] The structural diversity of natural products and their wide application in therapeutic has always been recognized by pharma industries.[3] Terpenoids account for the major class of secondary metabolites produced by plants [4] and have been widely considered as therapeutic agent. As per the World Health Organization report, extracts derived from folklore medicinal plants are widely used in indigenous therapies of 80% of the global population. Even today more than 50% of the modern approved clinical drugs have originated from natural sources.[5]

Terpenoids are organic compounds derived from five-carbon units (isoprene) assembled and modified in different ways. The classification of terpenoids is based on the isoprene units which are commonly classified as monoterpenoids (C10), for example, limonene, geraniol, and sesquiterpenoids; (C15), for example, artemisinin, humulene, and diterpenoids; (C20), for example, abietic acid, podocarpic acid, and sesterterpenoids; (C25), for example, manoalide and triterpenoids; and (C30), for example, squalene and cortisone.

Monoterpenoid

Monoterpenes comprise two isoprene units that may be linear or cyclic. These are abundantly available in essential oils and used for flavors, but a large number of bioactive compounds have been isolated that significantly was found active against specific cancer cell lines. These compounds have potential to act as a lead molecule for further drug development. Structure of all the compounds has been drawn and shown in [Figure 1]; [Table 1] shows the details of compounds.

In other study, β-pinene (3) was identified as major composition of oils achieved by hydrodistillation of Xylopia parviflora fruits. Against cancer cell line (MCF-7) and normal cell lines (adult retinal pigment epithelial-19), it showed cytotoxic activity with IC50 of 0.155 μL/mL and 0.166 μL/mL.[7]

From the fruit and bark of Rothmannia wittii, compound 10-O-acetylmacrophyllide (2) (4) was isolated which showed cytotoxic action showing IC50 value of 6.82 μg/mL in contradiction of the NCI-H187 cancer cell line.[8]

Ferula ovina roots led to the identification of stylosin (5). The compound on administration to 5637 cells showed IC50 values of 37, 35, and 31 μg/ml after 24, 48, and 72 h, respectively.[9]

Compound tabernaelegantine B (6) and D (7) were isolated from the stem bark of Muntafara sessilifolia that showed activity against MRC-5 cells with IC50 values of 0.47 and 1.89 μM and against L-6 cells IC50 values of 0.42 and 2.7 μM, respectively.[10]

Shoots of Plectranthus hadiensis-derived fraction were extracted which have major composition of geraniol (41.1%), geranyl acetate (29.5%), and nerol (10.4%) which showed activity against HCT-5 cell line with IC50 value of 17.27 ± 0.620 μg/mL.[11]

Diterpenoid

Basic skeleton of diterpenoid is made up of 20 carbons that consist of four isoprene units and are derivatived from geranylgeranyl pyrophosphate. They are found in almost all plant families. Anticancer compounds belonging to diterpenoid class have been discussed below. Structure of all the compounds has been drawn and shown in [Figure 2]; [Table 2] shows the details of compounds.

Caesalppans A–F (1–6) (11–16) was identified from seeds of Caesalpinia sappan. The compound was evaluated for its antiproliferative potential against cell lines HeLa, AtT20, and KB using the MTT method and showed IC50 value of 19.3–42.7 μM.[15]

Salyunnanins A–F, 1-6 (17–22) was extracted from roots of Salvia yunnanensis. The inhibitory potential of these metabolites in contradiction of HeLa, PC3, NCI-H460, MCF-7, KB-3–1, and K562 was evaluated in vitro. A range of IC50 values of 0.86–10.1 μM was observed.[16]

7-(2-oxohexyl)-11-hydroxy-6,12-dioxo-7,9 (11),13-abietatriene(=7-[2-oxohexyl]-taxodione) (23) was isolated from root culture of Agrobacterium rhizogenes-mediated root culture of Salvia austriaca. Compound exhibited high anticancer activity in contradiction to HL-60, NALM-6, and WM-115 with IC50 values between 0.63 and 0.72 μM.[17]

From the fruits of Rubus chingii, compound 15-O-β-d-apiofuranosyl-(1→2)-β-d-glucopyranosyl-18-O-β-d-glucopyranosyl-13(E)-ent-labda-8 (9),13 (14)-diene-3β, 15, 18-triol (3) (24) was obtained. Compound was found active against A549 cell line with an IC50 value of 2.32 μM.[18]

Methanolic extract from leaves of Blumea lacera resulted in the isolation of new compound 6E, 10E,14Z-(3S)-17-hydroxyge-ranyllinalool-17-O-β-d-glucopyranosyl-(1→2)-(α-l-rhamnopyranosyl-

[1→6])-β-d-glucopyranoside (1) (25) which was found potent against MCF-7 breast cancer cells with IC50 value of 8.3 μM.[19]

From fermentation of extract of Stevia rebaudiana new terpenes and sterebins O (1) (26), P1 (2) (27), and P2 (3) (28) were identified. Against B16 cell lines, all metabolites were found cytotoxic with IC50 values of 9.8 μM, 17 μM, and 75 μM.[20]

Sesquiterpene

Three isoprene units form a sesquiterpene. In higher plants, these are found in abundance. The precursor molecule for sesquiterpene is farnesyl pyrophosphate which by skeletal rearrangement gives rise to different structures. Structure of all the compounds has been drawn and shown in [Figure 3]; [Table 3] shows the details of compounds.

α-Santalol, (29) a sesquiterpene present in oil of sandalwood, showed to induce apoptosis in in vitro cell cultures. Breast cancer treated at the time interval of 6 h and 9 h with α-santalol showed downregulation of surviving in concentration-dependent manner. Downregulation by α-santalol is not directed through the PI3K-AKT pathway.[21]

Hoaensieremone (3) (30) was extracted from stems of Drypetes congestiflora. The compound was found active in contradiction to A549 and B16F10 cell lines showing IC50 values of 27.5 and 41.3 mm, respectively.[22] Two compounds, namely syreiteate A (1) (31) and syreiteate B (2) (32), were extracted from Ferula dissecta (Ledeb). Ledeb roots, both compounds, were found active against cervical cancer HeLa cell line showing 13.2 and 19.3 μM of IC50.[23]

From the leaves of Artemisia argyi, two new compounds, artemisinin A (1) (33) and isoartemisolide (2) (34), were isolated. Isoartemisolide (34) exhibited IC50 value of 4 μM in BV-2 microglial cells.[24]

α-Cadinol (35) was isolated from dried plant materials of Abies nephrolepis which showed inhibitory effect on Colo-205, A549, and QGY-7703 with IC50 values of 8.1, 8.6, and 4.6 μg/mL, respectively.[25]

New metabolite 1-oxoeudesm-11 (13)-ene-12,8α-lactone (7) (46) was found from the whole plant of Carpesium divaricatum. The compound showed inhibitory effect against KB and MCF-7 with IC50 values of 24.1 and 18.8 μM, respectively. The compound showed to activate mitochondria and generate reactive oxygen species to cause cell death in MCF-7 cells.[29]

Caesalpinone A (1) (47) was isolated from the pods of Caesalpinia spinosa Kuntze (Tara). 1D and 2D nuclear magnetic resonance (NMR) spectra were exploited to decipher structure of the compound. The compound showed inhibitory action against HL-60, SW-480, SMMC-7721, A549, and MCF-7 with IC50 of <40.[30]

In a study, new β-dihydroagarofuranoid sesquiterpenes (1a, 2a, 8b, 9b)-1, 8-bis (acetyloxy)-2, 9-bis (benzoyloxy)-14-hydroxy-b-dihydroagarofuran (50) was isolated from the whole plant of Aesculus californica, it inhibited the growth of MCF-7 cells with an IC50 of 17 ± 1 μM.[32]

Two sesquiterpene lactones linderolide G (1) (51) and lindestrene (16) (52) was isolated from the roots of Lindera strychnifolia. Spectroscopic observations followed by Cd analysis led to deciphering of the structure. Compound exhibited cytotoxic action against HSC-T6 with IC50 values of 2.9% and 73.1% inhibition at 100 μg/ml.[33]

A new sesquiterpene lactones dehydrooopodin (5) was obtained from Ferula oopoda roots. The configuration of this compound was deciphered by 1D and 2D NMR. Antiproliferative activity of compounds was tested against MCF-7 and K562 by alamarBlue assay. The compound isolated showed significant cytotoxicity with IC50 values of 15 and 5 mM, respectively.[35]

Triterpene

Structure of all the compounds has been drawn and shown in [Figure 4]; [Table 4] shows the details of compounds. Lupeol (54) was isolated from Dillenia indica L. Using sulforhodamine B method, ethanolic extract of fruits, stems, and leaves was evaluated for cytotoxicity against following sulforhodamine B method the cytotoxicity of ethanolic extracts of leaves, stems and fruits, was evaluated against two cell lines: colon carcinoma cell line (HCT-116) and liver carcinoma cell line (HEPG2) which showed an IC50 value of 9.8 μg and 20.1 μg respectively.[36]

A novel triterpene kaunial (57) was flowers of Kaunia lasiophthalma G. which was identified whose structure was deciphered by spectroscopic data. The cytotoxic activity was tested in contradiction to HCC1937, JIMT-1, L56Br-C1, MCF-7, and SK-BR-3 breast cancer cell line. It was compared against MCF-10A which is normal-like breast epithelial cell line. Compound 1 was found most potent against all evaluated cell line bearing IC50 value between 0.67 and 7.0 mM.[38]

New triterpenoids triregeloic acid (3) (67) was identified from the stems of Tripterygium regelii. Compound structure was identified by analyzing their NMR spectroscopic and HRESIMS data. The cytotoxicity was tested against MCF-7 which showed inhibitory effects of 24.1%.[42]

From the leaves and branches of Abies faxoniana, a novel triterpenoid 3-oxo-9-lanosta-722Z, 24-trien-26,23-olide (68) was isolated. Compound showed cytotoxicities in contradiction to MCF-7 and A549 cells showing IC50 values of 6.5 and 5.7 μM, respectively.[43]

The Abies faxoniana leaves and branches led to identification of compound neoabieslactone I whose structure was predicted by CD and spectroscopic technique. Compound was found active in contradiction to HCT-116, MCF-7, and A549 cell lines with IC50 values of 8.9, 7.6, and 4.2 μM, respectively.[50]

Conclusion

The inclination toward natural product has led the onset for the discovery of new bioactive metabolites that could be targeted for specific therapeutic use. As terpenoid is the largest class of secondary metabolites being produced by plants with its bioactivity against cancer cell lines, it serves a potential drug candidate. A number of compounds of terpenoid family have been highlighted in the review. Plant-based terpenoid constituents can subside nuclear factor-κB (NF-κB) signaling, the major regulator in the pathway of cancer. Various ranges of metabolites have been isolated, and their structures have been deciphered using the advance analytical techniques which serve a base in the development of drugs. The novel scaffolds identified could be treated as potential candidates for the treatment of various types of cancer. The future prospect offers the work to be carried out in areas of process optimization, epigenetic modification, better germplasm selection, and use of plant tissue culture technique to enhance the yield of bioactive metabolites to significant level. There is immense potential to use these metabolites in the development of cheaper more sustainable anticancer drug.